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Review ArticlePatient and Tumour Characteristics of Adult Head and Neck SoftTissue Sarcomas: A Systematic Review and Meta-Analysis
Sakshi Andersen,1 Henriette Mann,1 Anders Krarup-Hansen ,2 Christel Bræmer Lajer,1
and Christian Grønhøj 1
1Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen,Blegdamsvej 9, 2100 Copenhagen, Denmark2Department of Oncology, Herlev Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark
Correspondence should be addressed to Christian Grønhøj; [email protected]
Received 10 January 2019; Revised 17 March 2019; Accepted 31 March 2019; Published 22 May 2019
Academic Editor: C. Verhoef
Copyright © 2019 Sakshi Andersen et al. ,is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.
Background. Head and neck soft tissue sarcomas (HNSTS) constitute a rare and heterogeneous cancer entity. Managementremains a challenge due to the rarity and varied biological behaviour among various subtypes.,is systematic review examines thecharacteristics of tumours and patients with HNSTS. Materials and Methods. A systematic literature review and meta-analysiswere performed using the electronic databases PubMed and Embase. Eight eligible studies were identified, and 13 variables wereextracted from each study including 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate. Results. Weidentified eight studies (n� 1,120 patients; 739 males (66%)) from six different countries). In total, 24 histological subtypes werefound, and 20% of the sarcomas (n� 215) could not be subclassified. 607 sarcomas (57%) were <5 cm in diameter, and 945sarcomas (84%) were grade 3. 1,059 patients (90%) underwent surgery. Estimated 5-year OS was 74% (95% CI; 0.63–0.84%) and 5-year DFS was 56% (95% CI; 38–74%). Conclusion. HNSTS holds a relative poor prognosis possibly explained by the heterogeneityof the disease. Treatment of HNSTS has shown to be highly diverse, underlining the importance of uniformed treatment guidelinesin order to achieve improved survival outcomes.
1. Introduction
Head and neck soft tissue sarcomas (HNSTS) are a rareand heterogeneous group of malignancies accounting forapproximately 1% of all head and neck malignancies.HNSTS represents 10% of all soft tissue sarcomas [1].More than 80 histological subtypes are distinguished inthe 2013WHO classification [2]. Because of this rarity andthe diverse clinical behaviours, management of HNSTScan be challenging and should be carried out in a mul-tidisciplinary centre with expertise and experience insarcomas [3].
Surgery remains to be the primary treatment choice,even though it is difficult to achieve free surgical margins dueto the anatomy of the head and neck region [4]. Whencombined with surgery, radiotherapy may improve overall
prognosis for some HNSTS depending on the histologicaltype, whereas a better outcome is achieved for some his-tological subtypes when surgery is combined with chemo-therapy, e.g., angiosarcoma, rhabdomyosarcoma, andsynovial sarcoma [3, 5, 6].
,e purpose of this study was to systematically reviewthe literature on adult patients diagnosed with HNSTS andreport the distribution of histological subtypes, treatment,and overall survival (OS) rates.
2. Materials and Methods
2.1. Search Strategy and Eligibility Criteria. ,e electronicdatabases PubMed and Embase were used for searching.,e search strategy in PubMed included the followingkeywords: “Head and Neck,” “Oral Cavity,” “Pharynx,” and
HindawiSarcomaVolume 2019, Article ID 9725637, 8 pageshttps://doi.org/10.1155/2019/9725637
Tabl
e1:
Patient
data
andcharacteristics.
Mahmou
det
al.
[7]
And
raet
al.[8]
Gon
zalez-
Gon
zalezet
al.
[9]
Vitzthum
etal.
[10]
Tejani
etal.[6]
Penele
tal.[11]
Sidapp
aand
Krishnamurthy
[12]
Park
etal.[13]
Total
Cou
ntry
USA
Germany
Mexico
USA
USA
France
India
Korea
N%
Years
2004–2
013
2003–2
012
2004–2
009
1998–2
012
1999–2
009
1997–2
002
1996–2
005
1995–2
012
N%
N%
N%
N%
N%
N%
N%
N%
Cases
788
2651
4830
2827
122
1120
Male
539
6818
6931
6134
7120
6715
5417
6365
53739
66Medianage
6364
43.1
68.5
5045.7
3546
—<5
0181
23a
—34
67—
1240
1139
——
238
27>5
0607
77—
1733
b—
1860
1761
b—
—659
73Tu
mou
rsiz
e<5
cm443
56—
1529
c33
69c
1343
—17
6386
70c
607
57>5
cm345
44d
—36
7115
3111
37—
1037
3630
453
43Meantumou
rsiz
e(cm)
4.5e
4.6e
——
—2.7
4.8
—Grade
(FNCLC
C)
High/G3
788
100
1765
3059
2858
f23
7716
5721
78g
2218
945
84Interm
ediate/G
20
831
1020
03
108
290
5343
827
Low/G
10
14
1122
613
27
27
622
3025
585
Unspecified/un
know
n0
00
1429
27
27
017
1435
3Tstage
0—
——
——
——
——
1—
1454
1325
—12
40—
——
3923
2—
1246
3875
—18
60—
——
6840
3—
——
——
——
——
4—
——
——
——
——
Surgical
margins
†
R0497
6310
3935
6941
8517
57—
2074
7662
696
60R1
111
146
234
8—
723
—6
22h
2016
154
13R2
180
235
1913
253
6—
——
76
208
18Unspecified/un
know
n—
519
—4
8—
——
—9
15-year
OS
—82
—83
46—
6875
—5-year
DFS
——
—63
35—
65—
—Medianfollo
w-up(m
onths)
4539
23.8
57.6
—27
5972
—a ≤50,b≥5
0,c ≤5,
d ≥5,
e median,
f grade
2+3,
g grading
system
notspecified
inthearticle,a
ndh R
1+R2
.†R0
�negativ
esurgical
margins/clear
margins,R
1�microscop
icpo
sitivesurgical
margins/m
icroscop
icinvolved
margins,a
ndR2
�macroscop
icpo
sitivemargins/m
acroscop
icinvolved
margins.
2 Sarcoma
“Sarcoma.” �e search strategy in Embase included thekeywords “Head and Neck Sarcomas.” Studies publishedfrom 2000 until March 2018 reporting patient databases ofsoft tissue sarcomas in the head and neck region with aminimum of 20 patients (>18 years of age at diagnosis)were included. Studies reporting both localized disease andmetastatic disease were included. Exclusion criteria wereradiation-induced sarcomas, bone sarcomas, and studiesthat solely reported speci�c histological subtypes. Due to anupdate in WHO classi�cation of soft tissue tumours in1994, studies reporting patient cases from before 1994 wereexcluded.
2.2. Data Extraction. We extracted data on country, numberof cases, period, gender, age, histological subtypes, tumoursize, and grading according to the French Federation of CancerCentres Sarcoma Group (grade I, grade II, grade III, andunknown). Furthermore, T stage (0, 1, 2, 3, and 4), treatment(surgery, radiotherapy, and/or chemotherapy), surgical mar-gins (R0, R1, R2, and unspeci�ed/unknown), median followup, 5-year OS, and 5-year disease-free survival (DFS) were alsoextracted. We applied the model of random e�ects to performa meta-analysis of 5-year OS and 5-year DFS. Data analysiswas performed in Stata, and a p value< 0.05 was consideredstatistically signi�cant.
3. Results
We identi�ed 2,056 publications, of which eight studies(1,120 cases; 66% males) from six di�erent countries met theinclusion criteria. All studies reported the median age, whichranged from 35 to 68.5 years. In four studies (n� 897), 73%of the patients were more than 50 years of age (Table 1 andFigure 1).
Sarcomas with unidenti�ed histology (n� 215) anduncommon sarcoma subtypes (n� 141) constituted one-third of the cohort (n� 1,083) being the most frequenthistological subtypes.�ese were followed by �brosarcomas/�bromatous sarcomas (n� 136), vascular sarcomas(n� 125), and leiomyosarcomas (n� 89). Noteworthy, insome of the included studies, the group “uncommon sar-comas” consisted of several sarcoma subtypes traditionallyperceived as common sarcomas (e.g., rhabdomyosarcomas)(Table 2 and Figure 2). �is was mainly seen in studiesincluding a small number of cases. Hence, several of thecases classi�ed as “uncommon sarcomas” could potentiallybe reclassi�ed within one of the speci�ed subtypes.
In seven studies (n� 1,090), the median follow-up periodranged from 23.8 to 72months. Five-year OS was reported in�ve studies, 5-year DFS was reported in three studies, andtheir values were 74% (95% CI; 0.63–0.84%) and 56 % (95%CI; 38–74%), respectively (Table 1 and Figures 3 and 4).
Records identified through PubMed and Embase (n = 2,056)
Scre
enin
gIn
clud
edEl
igib
ility
Iden
tific
atio
n Additional records identified through other sources
(n = 4)
Records after duplicates removed(n = 1,844)
Records screened on basisof title and/or abstract
(n = 1,844)
Full-text articles assessed for eligibility
(n = 14)
Studies included in qualitative synthesis
(n = 8)
Studies included in quantitative synthesis (meta-analysis)
5-year OS (n = 5)5-year DFS (n = 3)
Records excluded(n = 6)
Review (n = 3)(i)Specific histological subtype (n = 1)
(ii)
Abstract (n = 2) (iii)
Records excluded(n = 1,829)
Figure 1: PRISMA 2009 ¡ow diagram.
Sarcoma 3
Six studies (n� 1,060) reported tumour size as a binaryoutcome (<5 cm or >5 cm), two studies reported mediantumour size, and one study reported both mean tumour sizeand tumour size as a binary outcome. In 57% of the cases, thetumour diameter was <5 cm in diameter at the time ofdiagnosis. Mean tumour size ranged from 2.7 to 4.8 cm(n� 55). Tumour grading was stated in all studies included(n� 1,120). 84% of the tumours were grade III, 7% weregrade II, 5% were grade I, and 3% were unspecified orunknown grade. ,e surgical resection margins were statedin seven studies (n� 1,092). 60% of the tumours had clear
surgical margins (R0), 13% had microscopic involvedmargins (R1), 18% had macroscopic involved margins (R2),and 1% had unknown margins (Table 1).
All studies (n� 1,120) reported treatment strategy(Table 3).
4. Discussion
To our knowledge, this is the first systematic review andmeta-analysis to explore patient and tumour characteristicsincluding OS, DFS, and treatment strategies for patients with
Table 2: Histological subtypes.
Mahmoudet al. [7]
Andraet al. [8]
Gonzalez-Gonzalez et al.
[9]∗Vitzthumet al. [10]∗
Tejaniet al.[6]
Penelet al.[11]∗
Sidappa andKrishnamurthy
[12]
Parket al.[13]
Total
Alveolar soft partsarcoma — — — — 1 — — 3 4
Angiosarcoma — 9 — 14 4 5 — 15 47Carcinosarcoma — — — — 1 — — — 1Chondrosarcoma — — — — — — — 8 8DFSP▪ — — — 1 — — 16 17Epithelioid sarcoma — — — — 1 1 — — 2Ewing’s sarcoma/PNET◊ — — — — — — — 4 4
Fibrosarcoma/fibromatoussarcoma○
125 — — — 1 2 1 7 136
Histiocytic sarcoma — — — — 1 — — — 1Leiomyosarcoma 76 — — 5 3 — 1 4 89Lipomatoussarcoma∆ 31 — — 3 4 — — 10 48
Low-gradefibromyxoid sarcoma — — — — — — — 2 2
MFH/undiff. pleo./UPS∞ — 5 — 9 — 2 6 3 25
Neurofibromatoussarcoma□ 46 — 9 1 — — 5 — 61
Osteosarcoma — — — — — — — 5 5Others• — 8 — 3 — — — 5 16Peripheralneuroectodermictumour
— — — — — 3 — — 3
Rhabdomyosarcoma — — 7 1 5 7 — 24 44Spindle cell — — — 4 3 — 10 9 26Synovial sarcoma 34 4 — 6 6 2 1 7 60Uncommon sarcomasubtypes† 139 — — — — — 2 — 141
Undifferentiatedsarcoma — — — — — 3 — — 3
Unidentifiedsarcoma◆ 215 — — — — — — — 215
Vascular sarcoma‡ 122 — — 2 — — 1 — 125∗Not all of the histological subtypes were reported. ▪Dermatofibrosarcoma protuberans. ◊Primitive neuroectodermal tumour. ○Including fibrosarcomaNOS, fibromyxoma, and fibrous histiocytoma. ∆Including myxosarcoma, angiomyxoma, atypical lipoma, liposarcoma NOS, fibromyxolipoma, myxoid,round cell, pleomorphic, mixed, and dedifferentiated liposarcoma, and spindle cell lipoma. ∞MFH �malignant fibrous histiocytoma, undiff.pleo. � undifferentiated pleomorphic sarcoma. UPS � unclassified pleomorphic sarcoma. □Including neurosarcoma and malignant peripheral nervesheath tumour. •Andra et al. [8], not otherwise specified; Vitzthum et al. [10], dendritic cell sarcoma, chordoma, and hemangioengothelioma; Park et al.[13], folicular dendritic cell sarcoma and teratocarcinosarcoma. †Including clear cell, dermatofibrosarcoma, rhabdomyosarcoma, epithelioid, desmo-plastic small round cell tumour, fascial, infantile, angiomatoid, fibrous histiocytoma, rhabdoid, giant cell tumour of soft part, and alveolar soft part.◆Sarcomatosis not otherwise specified (NOS), spindle cell, giant cell, small cell, and undifferentiated sarcoma. ‡Including hemangiosarcoma, malignanthemangioendothelioma, epithelioid hemangioendothelioma, malignant hemangiopericytoma, hemangiopericytoma, and lymphangiosarcoma.
4 Sarcoma
a HNSTS. In the meta-analysis, the pooled results showed a5-year OS of approximately 75% and a 5-year DFS of nearly50%.
Surgery remains the cornerstone of treatment of HNSTS,but the close relation to vital anatomic structures compli-cates this treatment strategy, explaining the relatively low 5-
4
47
1 8 172 4
136
1
89
48
225
61
516
3
4426
60
141
3
215
125
0
50
100
150
200
Alv
eola
r sof
t par
t sar
com
a
Ang
iosa
rcom
a
Carc
inos
arco
ma
Chon
dros
arco
ma
DFS
P
Epith
elioi
d sa
rcom
a
Ewin
g's sa
rcom
a/PN
ET
Fibr
osar
com
a/fib
rom
atou
s sar
com
a
Hist
iocy
tic sa
rcom
a
Leio
myo
sarc
om
Lipo
mat
ous s
arco
ma
Low
-gra
de fi
brom
yxoi
d sa
rcom
a
MFH
/und
iff.p
leo.
/UPS
Neu
rofib
rom
atou
s sar
com
a
Oste
osar
com
a
Oth
ers
Perip
hera
l neu
roec
tode
rmic
tum
or
Rhab
dom
yosa
rcom
a
Spin
dle c
ell
Syno
vial
sarc
oma
Unc
omm
on sa
rcom
a sub
type
s
Und
iffer
entia
ted
sarc
oma
Uni
dent
ified
sarc
oma
Vasc
ular
sarc
oma
Figure 2: Histological subtypes.
Study
Andra et al. [8] 0.85 (0.65, 0.96)
ES (95% CI)
0.83 (0.70, 0.93)
0.47 (0.28, 0.66)
0.70 (0.50, 0.86)
0.75 (0.67, 0.83)
0.74 (0.63, 0.84)
Vitzthum et al. [10]
Tejani et al. [6]
Sidappa and Krishnamurthy [12]
Park et al. [13]
Overall (I2 = 71.70%, p = 0.01)
0.25 0.5 0.75Proportion
1
Figure 3: 5-year overall survival.
Study
Vitzthum et al. [10]
Tejani et al. [6]
Sidappa and Krishnamurthy [12]
Overall (I2 = 73.96%, p = 0.02)
ES (95% CI)
0.65 (0.49, 0.78)
0.37 (0.20, 0.56)
0.67 (0.46, 0.83)
0.56 (0.38, 0.74)
0.5 0.75 10.25Proportion
Figure 4: 5-year disease-free survival.
Sarcoma 5
Tabl
e3:
Treatm
ent.
Mahmou
det
al.[7]
And
raet
al.[8]
Gon
zalez-
Gon
zalez
etal.[9]
Vitzthum
etal.[10]
Tejani
etal.[6]
Penel
etal.[11]
Sidapp
aand
Krishnamurthy
[12]
Park
etal.[13]
Total
N%
N%
N%
N%
N%
N%
N%
N%
N%
Surgery
788
100
2181
4894
3063
2480
1968
2696
103
841059
90Ra
diationtherapy
414
5326
2633
6534
7118
6014
5021
7865
53625
53Chemotherapy
126
1613
1312
242
410
338
290
—42
34213
18
6 Sarcoma
year DFS. Several factors influence the degree of surgicalresection, e.g., tumour location and size, the extend of in-vasion, and the performance status of the patient [14]. Eventhough surgery with wide resection margins remains adifficult task, this review shows that 90% of the patients weretreated with surgery (± radiation therapy and/or chemo-therapy), and wide surgical margins were obtained in 60% ofthe cases.
In the present study, 53% of the patients were treatedwith radiation therapy with or without surgery. Studies inpatients with truncal or extremity soft tissue sarcomas havedemonstrated an improved local control following adjuvantradiation therapy in patients with large grade II and grade IIIsarcomas. Furthermore, retrospective studies have shown anapproximately 10% improvement in OS following adjuvantradiation therapy in patients with grade III sarcomas [15].Similarly, radiation therapy has also been found to improveOS in HNSTS [7].
In order to improve 5-year DFS and 5-year OS, the valueof neoadjuvant chemotherapy in high-graded truncal orextremity soft tissue sarcomas has been investigated.However, the study was closed prematurely because supe-riority for neoadjuvant treatment was not to be expected[16]. Nevertheless, neoadjuvant chemotherapy still holds apotential improvement in the prognosis of HNSTS, andprospective, multicentre studies are needed in order to gaininformation about the effect of neoadjuvant treatment in-cluding chemotherapy and radiation therapy. Furthermore,in a study by Blay et al., early evaluation by a multidisci-plinary team demonstrated a significant improvement inrelapse-free survival [17]. Hence, HNSTS should only bemanaged by a specialist multidisciplinary environment inorder to ensure a uniform treatment protocol [18].
More than 80 histological subtypes of HNSTS have beenidentified [2]. In order to predict risk of metastasis andrelapse, it is important to identify the exact histologicalclassification. In this systematic review, 215 sarcomas couldnot be classified, and additional 141 sarcomas were classifiedas “uncommon sarcomas.” It is remarkable that one-third ofthe cohort constituted of sarcomas with unknown histologyand uncommon sarcoma subtypes. Noteworthy, the clas-sification of soft tissue sarcomas has evolved considerablyduring the past decades, especially due to evolvement inimmunohistochemical and genetic/molecular methods [19].It is likely that a large number of the cases included in thepresent review would be reclassified if classified today.Furthermore, many of the cases where a specific pathologicalclassification could not be obtained could probably beclassified using modern methods. ,is may complicateapplying the results of the present review on newly di-agnosed patients with HNSTS. A high expertise in histo-logical classification is crucial if more knowledge aboutbehaviour and treatment of sarcomas must be achieved. Itemphasizes the need of histological reevaluation of a specialtrained pathologist in the highest national level beforetreating and before publishing data of sarcomas.
,e present systematic review and meta-analysis holdimportant limitations. Inclusion and exclusion criteria aswell as staging and treatment varied between the included
studies, which complicates interpretation. ,e includedstudies reported a few cases of sarcomas, which were notclassified as soft tissue sarcomas; however, these constitutedonly a small part (1.3%) of the total cases included. ,eincluded studies originated from six countries, and themajority of the cases were obtained from a single study. Allstudies were retrospective, and the cases were obtainedduring long follow-up periods.
5. Conclusions
HNSTS is a rare and heterogeneous tumour group with greatdifferences in OS and DFS. ,e pooled results showed a 5-year OS of approximately 75% and a 5-year DFS of nearly50%. However, studies show varying prognoses demon-strating the difficulty in treating HNSTS underlining theimportance of uniformed treatment guidelines in order toachieve improved survival outcomes.
Conflicts of Interest
,e authors declare that there are no conflicts of interestregarding the publication of this article.
Authors’ Contributions
Sakshi Andersen and Henriette Mann contributed equally tothis work.
Acknowledgments
CG was funded by the nonprofit organization CandysFoundation and Kræftfonden (the Cancer Foundation).
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Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwww.hindawi.com
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